Compositions containing aromatic aldehydes and their use in treatments

ABSTRACT

Disclosed are pharmaceutical and cosmetic compositions containing aromatic aldehyde compounds. Some of the disclosed compositions are useful as topical therapeutics for treating inflammatory dermatologic conditions. Some of the compositions are useful in transdermal and other systemic dose forms for treating other inflammatory conditions in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/223,073, which was filed on Aug. 15, 2002, and which claims priorityunder 35 U.S.C. §119(e) to U.S. Provisional Application Ser. No.60/332,277, which was filed on Nov. 16, 2001, and to U.S. ProvisionalApplication Ser. No. 60/346,049, which was filed on Jan. 4, 2002, and toU.S. Provisional Application Ser. No. 60/368,518, which was filed onApr. 1, 2002, and to U.S. Provisional Application Ser. No. 60/384,589,which was filed on May 30, 2002, the disclosures of which areincorporated herein in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to aromatic aldehydes and their use as activeingredients in cosmetics and pharmaceuticals. More particularly, itconcerns such aldehydes and their use in cosmetics and as topical,transdermal or systemic pharmaceuticals.

2. State of the Art

This invention involves the use of aromatic aldehydes. Many aromaticaldehydes are known materials that commonly find use as chemicalintermediates. Some aromatic aldehydes are components of naturalproducts as well.

The present invention uses these aldehydes as active ingredients inpharmaceuticals and cosmetics. While the invention contemplates thatthese aldehyde materials can find application as systemic agents againstinflammatory conditions when delivered transdermally or orally or byinjection, at this time their preferred uses are as components oftopical cosmetic and pharmaceutical compositions used to treat a widerange of dermatological conditions ranging from dermatitis andU.V.-induced inflammation through psoriasis and acne.

Therapies used in the past to deal with conditions such as eczema andpsoriasis have included the use of simple emollients. Topical steroidsranging from mild agents such as hydrocortisone (1%) through more potentmaterials such as clobetasol propionate (0.05%) have been indicated withthe common inflammatory dermatoses. In addition, corticosteroids andimmunosuppresents have been used to treat skin conditions. Vitamin D andits derivatives such as calcipotrial and tacolcitol and vitamin A andother retinoids have been used to treat dermatological problems. Thevitamin D materials are used to treat acne.

In addition to those directly topical therapies, it is well known thatmany materials pass through the skin and enter the systemic circulationwhen placed on the skin. The line between “topical” and this so called“transdermal” administration of drugs is a fuzzy one and many therapiesheretofore have had both topical and transdermal aspects.

These therapies are not without their limitations. Emollients are verytemporary and must be repeatedly renewed. Topical steroid use isassociated with thinning skin, bruising, and rashes as well as serioussystemic side effects such as development of Cushing's Syndrome.

The vitamin D materials often pass transdermally and can have unexpectedeffects on the user's systemic calcium metabolism. The retinoids arereported to cause acne in some cases and to produce teratogenic effectsif absorbed transdermally during pregnancy.

It is clear that there is a need for additional topical compositionswhich can effectively treat dermatological conditions. It would behighly desirable if these compositions could also treat and optionallytransdermally or otherwise systemically treatable inflammatoryconditions and avoid some or all of the problems associated withtherapies now in use.

SUMMARY OF THE INVENTION

It has now been found that a group of aromatic aldehydes are effectivetopical agents against inflammation-related dermatological conditions.These aldehydes also appear to be delivered to a measurable extenttransdermally and thus to potentially achieve systemic and/or localizedanti-inflammatory effects within the body. In view of these findings, itfurther appears that these aldehydes can be effective against otherinflammatory conditions when administered by other systemic routes.

In one of its composition aspects, this invention is directed to topicalpharmaceutical and cosmetic compositions containing apharmaceutically-acceptable topical carrier and one or more aromaticaldehyde compounds. These aromatic aldehydes include materials ofFormula I, as well as protected versions, that is, acetals as in FormulaII, and hemiacetals as in Formula III:

wherein

R¹ is a carbon-carbon single bond or a straight chain or branched chainalkylene;

R² is a carbon-oxygen single bond or a straight chain or branched chainalkylene;

R³ is a straight chain or branched chain alkyl, a cycloalkyl, analkcycloalkyl, an alkenyl, an aryl or an aralkyl; and

each R⁴ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkcycloalkyl, cycloalkyl, alkoxy,alkcycloalkoxy, cycloalkoxy, acyl acyloxy and halogen; and

each R⁵ is independently alkyl, or in the case of the acetals of FormulaII, the two R⁵s together with the atoms to which they are attached forma heterocycloalkyl;

subject to the proviso that the compound of Formula I is neither

2-4-diethoxybenzaldehyde, nor

2,4,5-triethoxybenzaldehyde.

In another of its composition aspects, this invention is directed topharmaceutical compositions for topical, transdermal or other systemicadministration containing a pharmaceutically-acceptable carrier and oneor more of the aromatic aldehyde compounds of Formula I, II or III,excluding formulations where the compound of Formula I is4-methoxybenzaldehyde for use systemic administration.

In one of its method aspects, this invention is directed to a method fortreating a patient with a dermatological disease which method comprisestopically administering to said patient a pharmaceutical compositioncomprising a pharmaceutically acceptable topical carrier and aneffective dermatological disease-treating amount of a compound ofFormula I, II or III above.

In another one of its method aspects, this invention is directed to amethod for treating a dermatological condition, which method comprisestopically applying to a human a cosmetic composition comprising apharmaceutically acceptable topical carrier and an effective amount of acompound of Formula I, II or III above.

In still another of its method aspects, this invention is directed to amethod for treating a patient with an inflammatory disease which methodcomprises systemically administering to said patient a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and aneffective inflammatory disease-treating amount of a compound of FormulaI, II or III above, excluding the compound 4-methoxybenzaldehyde.

In yet another of its method aspects, this invention is directed to amethod for treating a human with an inflammatory condition which methodcomprises topically applying to said human a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and an effective amountof a compound of Formula I, II or III above.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1: A schematic diagram illustrating inflammatory processes in theskin and showing the relationship of inflammation to the release ofvarious proteins.

FIG. 2: A repeat of FIG. 1 illustrating those inflammatory processeswhich are effectively treated using the present invention.

FIG. 3 and FIGS. 4A and 4B: Bar graphs which show the effects ofaldehydes employed in the compositions of this invention on interleukin1 “1L-1”-induced prostaglandin E2 “PGE₂” expression in dermalfibroblasts.

FIG. 5: A bar graph which shows the effects of aldehydes employed in thecompositions of this invention on tetradecanoyl phorbol acetate“TPA”-induced PGE₂ expression in keratinocytes.

FIG. 6: A table which shows the effects of aldehydes employed in thecompositions of this invention and other related compounds on expressionlevels of varius proteins in fibroblasts challenged with 1L-1 or UVlight.

FIG. 7: A table which shows the effects of aldehydes employed in thecompositions of this invention and other related compounds on expressionlevels of varius proteins in keratinocytes challenged with TPA or UVlight.

FIGS. 8A, 8B, 9A, 9B, 10A, 10B, 11A and 11B: Bar graphs of datatabulated in FIG. 6.

FIGS. 12A, 12B, 13A, 13B, 14A and 14B: Bar graphs of data tabulated inFIG. 7.

FIGS. 15A and 15B: Bar graphs of data obtained in an in vivo test of thelotion formulation of Example 8.

DETAILED DESCRIPTION OF THE INVENTION Definitions

When describing the aromatic aldehyde compounds employed in the cosmeticand pharmaceutical compositions and methods of this invention as well asthe compositions and methods themselves, the following terms have thefollowing meanings:

“Acyl” refers to the group —C(O)R where R is hydrogen, alkyl or aryl.When R is hydrogen this is a “formyl”, when R is CH₃ this is “acetyl”.

“Acyloxy” refers to the group —O-Acyl.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbon groupspreferably having from 1 to about 20 carbon atoms, more preferably from1 to 12, even more preferably 1 to 8 carbon atoms. This term isexemplified by groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and thelike. The term “lower alkyl” refers to alkyl groups having 1 to 6 carbonatoms and especially 1 to 4 carbon atoms.

“Substituted alkyl” refers to an alkyl group, preferably of from 1 toabout 20 carbon atoms, having from 1 to 5 substituents, and preferably 1to 3 substituents, selected from the group consisting of alkoxy,cycloalkyl, cycloalkoxy, acyl, aminoacyl, amino, aminocarbonyl, cyano,halogen, hydroxyl, carboxyl, keto, thioketo, alkoxycarbonyl, thiol,thioalkoxy, aryl, aryloxy, nitro, —OSO₃H and pharmaceutically acceptablesalts thereof, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, and mono- and di-alkylamino, mono-and di-arylamino, and unsymmetric di-substituted amines having differentsubstituents selected from alkyl, substituted alkyl and aryl.

“Alkenyl” refers to monovalent unsaturated aliphatic hydrocarbon groupshaving from 1 to 20 carbon atoms and preferably 1 to 6 carbon atoms and1 to 2 and especially 1 olefinic unsaturation.

“Alkylene” refers to divalent saturated aliphatic hydrocarbon groupspreferably having from 1 to 20 carbon atoms and more preferably 1 to 6carbon atoms which can be straight chain or branched. This term isexemplified by groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

“Alkcycloalkyl” refers to -alkylene-cycloalkyl groups preferably havingfrom 1 to 20 carbon atoms in the alkylene moiety and from 3 to 8 carbonatoms in the cycloalkyl moiety. Such alkcycloalkyl groups areexemplified by —CH₂-cyclopropyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclohexyl,and the like.

“Alkcycloalkoxy” refers to —O-alkylene-cycloalkyl groups preferablyhaving from 1 to 20 carbon atoms in the alkylene moiety and from 3 to 8carbon atoms in the cycloalkyl moiety. Such alkcycloalkoxy groups areexemplified by —OCH₂-cyclopropyl, —OCH₂-cyclopentyl,—OCH₂CH₂-cyclohexyl, and the like.

“Alkoxy” refers to the group “alkyl-O—”. Preferred alkoxy groupsinclude, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy,1,2-dimethylbutoxy, and the like.

“Alkoxycarbonyl” refers to the group —C(O)OR where R is alkyl.

“Aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen or alkyl.

“Aminoacyl” refers to the group —NRC(O)R where each R is independentlyhydrogen or alkyl.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl). Preferred aryls includephenyl, naphthyl and the like. Unless otherwise constrained by thedefinition for the individual substituent, such aryl groups canoptionally be substituted with from 1 to 3 substituents selected fromthe group consisting of alkyl, alkoxy, alkaryloxy, alkenyl, alkynyl,amino, aminoacyl, aminocarbonyl, alkoxycarbonyl, aryl, carboxyl,cycloalkoxy, cyano, halo, hydroxy, nitro, trihalomethyl, thioalkoxy, andthe like.

“Aralkyl” refers to the group “alkylene-aryl” and is most typicallybenzyl.

“Aryloxy” refers to —O-aryl groups wherein “aryl” is as defined above.

“Carboxyl” refers to the group —C(O)OH.

“Cyano” refers to the group —CN.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 20 carbon atomshaving a single cyclic ring or multiple condensed rings, including fusedand bridged ring systems, which can be optionally substituted with from1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example,single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,2-methylcyclooctyl, and the like, or multiple ring structures such asadamantanyl, and the like.

“Cycloalkoxy” refers to —O-cycloalkyl groups. Such cycloalkoxy groupsinclude, by way of example, cyclopentyloxy, cyclohexyloxy and the like.

“Heterocycloalkyl” refers to cyclic groups of from 2 to 10 carbon atomsand 1, 2 or 3 heteroatoms selected from nitrogen, sulfur, orphosphorous, especially oxygen, for example. The ring can be optionallysubstituted with from 1 to 3 alkyl groups. Such heterocycloalkyl groupsinclude, by way of example, single ring structures such astetrahydrofuran, 1,4 dioxacyclopentanyl, dioxane, pyrrolidine,tetrahydrothiophene, and the like.

“Ionizing radiation” refers to any radiation that ionizes the atoms ormolecules of matter. It may consist of particles (such as electrons) orit may be electromagnetic (ultraviolet radiation; X-rays; gammaradiation). Ionizing radiation occurs naturally, for example as acomponent of sunlight, and is emitted by radioactive substances. It isalso produced artificially in X-ray machines, particle accelerators,nuclear reactors, etc.

“Isolated”, when used to define the state of purity of the aromaticaldehyde compounds used in the practice of this invention, means thatthe aromatic aldehyde has been substantially freed of (i.e at leastabout 90% and especially at least about 95% freed of) or separated fromrelated feedstocks, co-products, or in the case of naturally-occurringmixtures, related materials with which the aldehyde appears in nature.

“Pharmaceutically-acceptable topical carrier” and equivalent terms referto an inactive liquid or cream vehicle capable of suspending ordissolving the aromatic aldehyde and having the properties of beingnontoxic and noninflammatory when applied to the skin. This term isspecifically intended to encompass carrier materials approved for use intopical cosmetics. Representative carriers include water, oils, bothvegetable and mineral, cream bases, lotion bases, ointment bases and thelike. These bases include suspending agents, thickeners, penetrationenhancers, and the like. Their formulation is well known to those in theart of cosmetics and topical pharmaceuticals. Additional informationconcerning carriers can be found in Part 8 of Remington's PharmaceuticalSciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa.,which is incorporated herein by reference.

“Therapeutically effective dose” means a dose of a composition of thisinvention which, when applied topically to the skin of a patientafflicted with a dermatologic or other cosmetic or medical condition, orwhen administered by another route, results in an observable improvementin the patient's condition.

“Topical”, when used to define a mode of administration, means that amaterial is administered by being applied to the skin.

“Topically effective” means that a material, when applied to the skin,produces a desired pharmacological result either locally at the place ofapplication or systemically as a result of transdermal passage of anactive ingredient in the material.

The Aromatic Aldehydes

The aromatic aldehydes include the compounds of Formula I as well astheir acetal and hemiacetal equivalents shown in Formulas II and III.

Preferably, in the aromatic aldehyde compounds of Formula I above, R¹ isselected from the group consisting of a carbon-carbon single bond,methylene and ethylene. More preferably, R¹ is a carbon-carbon singlebond.

Preferably, R² is selected from the group consisting of a carbon-oxygensingle bond, methylene and ethylene. More preferably, R² is acarbon-oxygen single bond.

Preferably, R³ is alkyl. More preferably, R³ is methyl, ethyl or apropyl.

The four R⁴ s preferably include at least 2 hydrogens. More preferably,the remaining two R⁴s are each independently, hydrogen, alkyl or alkoxy.Still more preferably, each of the four R⁴s is hydrogen.

Preferably, each R⁵ is independently alkyl, or in the case of theacetals of Formula II, the two R⁵s together with the atoms to which theyare attached form a heterocycloalkyl. More preferably each of the R⁵stogether with the atoms to which they are attached form1,4-dioxacyclopentanyl or a substituted 1,4-dioxacyclopentanyl.

An especially preferred group of compounds of Formula I are those inwhich R¹ is a carbon-carbon single bond; R² is a carbon-oxygen singlebond located in the 4 position on the aromatic ring relative to thealdehyde functionality, R³ is methyl or ethyl and at least two R⁴′s areeach hydrogen.

In another of its composition aspects, this invention is directed tocosmetic and pharmaceutical compositions comprising a suitable carrierand containing one or more of the following aromatic aldehyde compounds:

2-methoxybenzaldehyde

2-ethoxybenzaldehyde

2-propoxybenzaldehyde

2-isopropoxybenzaldehyde

3-methoxyhenzaldehyde

3-ethoxybenzaldehyde

3-propoxybenzaldehyde

3-isopropoxybenzaldehyde

4-ethoxybenzaldehyde

4-propoxybenzaldehyde

4-isopropoxybenzaldehyde

2-methoxy-3-methylbenzaldehyde

2-ethoxy-3-methylbenzaldehyde

2-propoxy-3-methylbenzaldehyde

2-isopropoxy-3-methylbenzaldehyde

3-methoxy-4-methylbenzaldehyde

3-ethoxy-4-methylbenzaldehyde

3-propoxy-4-methylbenzaldehyde

3-isopropoxy-4-methylbenzaldehyde

2-butoxybenzaldehyde

4-butoxybenzaldehyde

4-pentyloxybenzaldehyde

4-hexyloxybenzaldehyde

4-heptyloxybenzaldehyde

3-ethoxy-4-methoxybenzaldehyde

4-ethoxy-3-methoxybenzaldehyde

3,4-diethoxybenzaldehyde

3-ethoxy-4-hexyloxybenzaldehyde

2-fluoro-4-methoxybenzaldehyde

2-fluoro-4-ethoxybenzaldehydc

2-fluoro-4-heptyloxybenzaldehyde

2-fluoro-4-octyloxybenzaldehyde

4-(methoxymethyl)benzaldehyde

4-(ethoxymethyl)benzaldehyde

3-(dodecyloxy)benzaldehyde

2,3-dimethoxybenzaldehyde

3,5-dimethoxybenzaldehyde

3-benzyloxy-4,5-dimethoxybenzaldehyde

4-benzyloxy-benzaldehyde

4-acetoxy-3,5-dimethoxybenzaldehyde

4-allyloxybenzaldehyde

3,4-dimethoxybenzaldehyde

2-carboxyl-3,4-dimethoxybenzaldehyde

2,4,5-trimethoxybenzaldehyde

3-chloro-4-methoxybenzaldehyde

3-butyloxy-4-methoxybenzaldehyde

3,5-dimethoxy-4-benzoxybenzaldehyde

2-acetoxy-3-methoxybenzaldehyde

3,5-dichloro-4-methoxybenzaldehyde

2-methyl-3,5-dimethoxybenzaldehyde

2,3,4,5-tetramethoxybenzaldehyde

2-formyl-3,6-dimethoxy-4,5-dimethylbenzaldehyde

2-acetyloxy-3-methoxy-6-bromobenzaldehyde

2-methoxy-6-(8-pentadecenyl)benzaldehyde

2-methoxy-5-acetylbenzaldehyde

2,5-dimethoxy-4-formylbenzaldehyde

4-octyloxybenzaldehyde

2-propoxy-5-carboxybenzaldehyde

2-butoxy-5-carboxybenzaldehyde

2-pentoxy-5-carboxybenzaldehyde

2-hexoxy-5-carboxybenzaldehyde

3-(4-methoxyphenoxy)benzaldehyde

3 -(4-tertbutylphenoxy)benzaldehyde

as active ingredients

Preferred aldehydes include: 2-ethoxybenzaldehyde,2-acetoxy-3-methoxybenzaldehyde, 4-allyloxy-benzaldehyde,4-ethoxybenzaldehyde, 4-propoxybenzaldehyde, 4-butoxybenzaldehyde,4-pentyloxybenzaldehyde, and 4-hexyloxybenzaldehyde.

The aromatic aldehydes are generally employed as isolated compoundsmixed with a suitable carrier.

2-methoxybenzaldehyde is among the aldehydes used herein. This is asynthetic flavoring substance approved by the Food and DrugAdministration (FDA) for use in food for humans. The details for its useare discussed in Title 21 of the Code of Federal Regulations (CFR),chapter 1 part 172 subpart F Sec. 172.515.

General Synthetic Procedures

The aromatic aldehydes employed in the compositions and methods of thisinvention are either known compounds or are compounds that can beprepared from readily available starting materials using the followinggeneral methods and procedures. It will be appreciated that wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvent used, but such conditions can be determined by one skilled inthe art by routine optimization procedures.

For example, such compounds are readily prepared by acylation of thecorresponding aryl compound with the appropriate acyl halide underFriedel-Crafts acylation reaction conditions. Additionally, the formylcompounds, i.e. those compounds where R⁴ is hydrogen, can be prepared byformulation of the corresponding aryl compound using, for example, adisubstituted formamide, such as N-methyl-N-phenylformamide, andphosphorous oxychloride (the Vilsmeier-Haack reaction), or using Zn(CN)₂followed by water (the Gatterman reaction). Numerous other methods areknown in the art for preparing such aryl carbonyl compounds. Suchmethods are described, for example, in I. T. Harrison and S. Harrison,Compendium of Organic Synthetic Methods, Wiley, N.Y., 1971, andreferences cited therein.

Certain aromatic aldehyde compounds of Formula I can also be prepared byalkylation of the corresponding aryl hydroxy compound (e.g.,4-hydroxybenzaldehyde and the like). This reaction is typicallyconducted by contacting the aryl hydroxy compound with a suitable base,such as an alkali or alkaline earth metal hydroxide, fluoride orcarbonate, in a inert solvent, such as ethanol, DMF and the like, todeprotonate the hydroxyl group. This reaction is generally conducted atabout 0° C. to about 50° C. for about 0.25 to 2 hours. The resultingintermediate is then reacted in situ with about 1.0 to about 2.0equivalents of an alkyl halide, preferably an alkyl bromide or iodide,at a temperature of from about 25° C. to about 100° C. for about 0.25 toabout 3 days.

Additionally, various aromatic aldehydes of Formula I can be prepared byreduction of the corresponding aryl nitriles. This reaction is typicallyconducted by contacting the aryl nitrile with about 1.0 to 1.5equivalents of a hydride reducing agent, such as LiAlH(OEt)₃, in aninert solvent such as diethyl ether, at a temperature ranging from about−78° to about 25° C. for about 1 to 6 hours. Standard work-up conditionsusing aqueous acid then provides the corresponding aryl aldehyde.

The aromatic aldehydes of Formula II and III employed in thecompositions and methods are either known compounds or compounds thatcan be prepared from known compounds by conventional procedures. Thehemiacetals can be formed by either acid or base catalyzed reaction ofthe corresponding aldehyde with and alcohol. If a single equivalent ofthe alcohol is added to the carbonyl, the hemiacetal is formed. Additionof 2 equivalents of an alcohol to the carbonyl produces the acetal.Acetal formation is acid catalyzed and is typically conducted by adding1 mol of aldehyde and a 0.1 mol of CaCl₂ to 1.9 mol of ethanol. Thereaction mixture is held at room temperature for 1 to 2 days. Standardwork up conditions provide the acetal protected aromatic aldehyde.

Pharmaceutical and Cosmetic Compositions and Their Use

The aromatic aldehydes are administered in the form of a pharmaceuticalor cosmetic composition. Such compositions can be prepared in mannerswell known in the pharmaceutical and cosmetic arts and comprise at leastone active compound.

Generally, the compositions of this invention are administered in acosmetic amount or in a therapeutically effective dose. The amount ofthe compound actually administered in therapeutic settings may typicallybe determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like. In cosmetic settings the amount to be applied isselected to achieve a desired cosmetic effect.

The cosmetic compositions of this invention are to be administeredtopically. The pharmaceutical compositions of this invention are to beadministered topically, transdermally or systemically such as orally orby injection.

In such compositions, the aromatic aldehyde compound is usually a minorcomponent (from about 0.001 to about 20% by weight or preferably fromabout 0.01 to about 10% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

Topical cosmetic forms and topical pharmaceutical dosing forms caninclude lotions, shampoos, soaks, gels, creams, ointments and pastes.Lotions commonly employ a water or alcohol base. Gels are semi-solidemulsions or suspensions. Creams generally contain a significantproportion of water in their base while ointments and creams arecommonly more oily.

Liquid forms, such as lotions suitable for topical administration or forcosmetic application, may include a suitable aqueous or nonaqueousvehicle with buffers, suspending and dispensing agents, thickeners,penetration enhancers, and the like. Solid forms such as creams orpastes or the like may include, for example, any of the followingingredients, water, oil, alcohol or grease as a substrate withsurfactant, polymers such as polyethylene glycol, thickeners, solids andthe like. Liquid or solid formulations may include enhanced deliverytechnologies such as liposomes, microsomes, microsponges and the like.

The above-described components for liquid, semisolid and solid topicalcompositions are merely representative. Other materials as well asprocessing techniques and the like are set forth in Part 8 ofRemington's Pharmaceutical Sciences, 17th edition, 1985, Mack PublishingCompany, Easton, Pa., which is incorporated herein by reference.

When pharmaceutical compositions are to be administered transdermallythey typically are employed as liquid solutions or as gels. In thesesettings the concentration of active aldehyde ranges from about 0.1% toabout 20%, and preferably from about 0.1% to about 5%, of thecomposition with the remainder being aqueous mixed or nonaqueousvehicle, such as alcohols and the like, suspending agents, gellingagents, surfactant, and the like. Examples of suitable such materialsare described below.

The aldehyde-containing compositions of this invention can also beadministered in sustained release transdermal forms or from transdermalsustained release drug delivery systems. A description of representativesustained release materials can be found in the incorporated materialsin Remington's Pharmaceutical Sciences.

The compositions for systemic administration include compositions fororal administration, that is liquids and solids, and compositions forinjection.

Compositions for oral administration can take the form of bulk liquidsolutions or suspensions, or bulk powders. More commonly, however, thecompositions are presented in unit dosage forms to facilitate accuratedosing. The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical occupant. Typical unit dosage forms includeprofiled, premeasured ampules or syringes of the liquid compositions orpills, tablets, capsules or the like in the case of solid compositions.In such compositions, the aromatic aldehyde is usually a minor component(from about 0.01 to about 20% by weight or preferably from about 0.1 toabout 15% by weight) with the remainder being various vehicles orcarriers and processing aids helpful for forming the desired dosingform.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an occupant such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the aromatic aldehyde in such compositions istypically a minor component, often being from about 0.005 to 5% byweight with the remainder being the injectable carrier and the like.

The above-described components for orally administrable or injectablecompositions are merely representative. Other materials as well asprocessing techniques and the like are set forth in the part ofRemington's Pharmaceutical Sciences noted above.

The following formulation examples illustrate representative cosmeticand pharmaceutical compositions of this invention. The presentinvention, however, is not limited to the following pharmaceuticalcompositions.

Formulation 1 Liquid

A compound of Formula I (125 mg), and xanthan gum (4 mg) are blended,passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of microcrystalline cellulose and sodiumcarboxymethyl cellulose (11:89, 50 mg) in a water/isopropanol (75:25)mixture. Sufficient water/isopropanol are then added to produce a totalvolume of 5 mL.

Formulation 2 Cream

A commercial mineral oil-water cold cream base is obtained. To 100 gramsof this base, 0.75 grams of a compound of Formula I as a fine powder orliquid is added with continuous mixing and stirring to suspend thepowder in the base and yield a cosmetic or pharmaceutical composition.

This composition includes the following: deionized water (57.6% byweight); niacinamide (2.0%); glycerin (4.0%); phenonip (1.0%); propyleneglycol (5.0%); transcutol (3.2%); jojoba Oil (3.5%); isocetyl alcohol(2.0%); isocetyl stearate (3.5%); mineral oil (3.0%);4-ethoxybenzaldehyde (1.0%); isostearyl palmitate (3.0%); PEG-7 glycerylcocoate (2.0%); Glycereth-7 (2.0%); POLYSORBATE-20™ (0.2%); cetylricinoleate (1.0%); glyceryl stearate/PEG-100 stearate (4.0%); andSEPIGEL™ (2.0%).

Formulation 3 Tablets

A compound of Formula I is mixed with dry gelatin binder and starchdiluent in a 0.1: 1:1 weight ratio. A lubricating amount of magnesiumstearate is added and the mixture is tabletted into 210 mg tabletscontaining 10 mg of active aromatic aldehyde.

Formulation 4 Injection

A compound of Formula I is dissolved in injectable aqueous saline mediumat a concentration of 1 mg/ml.

Utility and Dosing

The composition and methods of this invention can be used topically totreat dermatological conditions such as

-   -   actinic keratosis,    -   acne,    -   allergic contact dermatitis,    -   atopic eczema,    -   contact dermatitis,    -   eczema,    -   erythema,    -   hand eczema,    -   itch,    -   irritant contact dermatitis,    -   psoriasis,    -   seborrhoric eczema,    -   rosacea,    -   alopecia areata,    -   damage from radiation, including UV radiation, IR radiation and        any other ionizing radiation,    -   and the like.

The compositions, both cosmetic and pharmaceutical, can also be used totreat and prevent sunburn and to treat and prevent other forms ofUV-induced inflammation and damage, and damage from other forms ofionizing radiation.

In these applications the cosmetic and pharmaceutical compositions areadministered topically to achieve a desired cosmetic effect or a topicaltherapeutic effect.

In these uses the dose levels or application levels can be expressed interms of the amount of active aromatic aldehyde delivered to the skin.For example, 1 to about 5 doses or applications per day, each containingfrom about 0.001 g to about 1 gram of active aldehyde can be used.

Alternatively, dose levels can be expressed in terms of the volume offormulated composition administered. For example, 1 to about 5 doses orapplications per day, each containing from about 1 to about 30 grams ofcomposition containing from about 0.01% to about 10% by weight of activealdehyde and especially from 0.02% to about 8% by weight.

When used in a sun care product, such as sun-care lotion, theconcentration of aldehyde can be as set forth above and the product canbe applied as needed based on the intensity and duration of sunexposure.

Additionally, since the aromatic aldehydes have been discovered toeffectively inhibit the release of cytokines, such a IL-1α, suchcompounds are useful for treating diseases characterized by anoverproduction or a dysregulated production of cytokines, particularlyIL-1α. Elevated levels of IL-1 and other cytokines are associated with awide variety of inflammatory conditions, including rheumatoid arthritis,septic shock, erythema nodosum leprosy, septicemia, adult respiratorydistress syndrome (ARDS), inflammatory bowel disease (IBD), uveitis,damage from ionizing radiation and the like.

The relationships between these cytokines and related materials and theinflammatory processes are described in more detail below at “Biologyand Testing”.

In the case of transdermal administration to treat such inflammatoryconditions, one can administer a quantity of composition to a surfacearea of skin suitable to achieve an active aldehyde concentration in thesystemic bloodstream of from about 0.5 to about 1000 micromolar andespecially from about 1 to about 500 micromolar.

Injection dose levels for treating inflammatory conditions range fromabout 0.01 mg/kg/hour to at least 1 mg/kg/hour, all for from about 1 toabout 120 hours and especially 24 to 96 hours. A preloading bolus offrom about 0.01 mg/kg to about 1 mg/kg or more may also be administeredto achieve adequate steady state levels.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 10 mg/kg of thearomatic aldehyde, with preferred doses each providing from about 0.01to about 5 mg/kg.

The aromatic aldehydes can be administered as the sole active agent orthey can be administered in combination with other agents.

Biology and Testing

The examples include a number of in vitro studies to investigate theability of these aldehydes to block various inflammatory processes inthe skin. For these studies primary human keratinocytes and dermalfibroblast cell strains have been used as well as THP-1 monocytes andthe Jurkat T-cell derived cell line. The in vitro experiments used toassess the anti-inflammatory activities of the aldehydes were selectedon the basis of current knowledge about the skin inflammatory process.FIG. 1 depicts the events involved in cutaneous inflammation.

Inflammation in the skin is characterized by itching, pain, redness,swelling and, frequently, rough and flaky skin. These symptoms resultfrom changes in blood flow to the site of inflammation, increasedvascular permeability, the migration of cells from the circulation intothe tissue, and the release of soluble mediators including cytokines,prostaglandins and chemokines. Skin inflammation can be triggered by: 1)infection caused by bacteria, parasites, fungi, or viruses, 2) injuryresulting from physical trauma including burns, UV and ionizingradiation, 3) contact with chemical irritants, and 4) exposure to aforeign body such as an allergen which triggers an immune response.

Inflammation can be characterized as acute or chronic. Acute skininflammation can result from exposure to UV radiation (UVR), ionizingradiation or contact with chemical irritants and allergens. In contrast,chronic inflammation results from a sustained immune cell mediatedinflammatory response. Acute inflammatory responses are typicallyresolved within 1 to 2 weeks with little accompanying tissuedestruction. Chronic inflammatory responses, however, are long-lastingbecause the antigen that triggered the response persists in the skin.This leads to continued recruitment of immune cells into the tissue,particularly T lymphocytes, which then produce and secrete high levelsof many inflammatory mediators. Chronic inflammation leads tosignificant and serious tissue destruction.

Regardless of the stimulus that triggers either an acute or chroniccutaneous inflammatory response, the initial events are similar and areshown in FIGS. 1 and 2. Triggering stimuli, such as UV radiation, inducekeratinocytes in the skin to produce various cytokines including the keyinflammatory cytokine, Interleukin-1 (IL-1). These cells also produceTumor Necrosis Factor (TNF-α) and prostaglandin E2 (PGE-2). PGE-2 causesvasodilation of blood vessels near the site of injury and also increasesthe sensitivity of sensory nerve endings resulting in the sensation ofitching and pain. The principal action of TNF-α is to increase theproduction of adhesion molecules on the surface of endothelial cellslining the blood vessels. These adhesion molecules act as anchors withinthe blood vessel allowing immune cells moving through the circulation toattach to the endothelium, an event that can lead to the diapedsis(movement) of these cells from the circulation and into the tissue. IL-1produced by keratinocytes binds to specific receptors on fibroblastswithin the dermis and activates signaling pathways that lead to theinduction of many pro-inflammatory genes, such as those for COX-2, IL-8and IL-6. IL-1 also binds to specific receptors on mast cells resultingin the production and secretion of histamine (which also increases nerveending sensitivity), cytokines and other inflammatory mediators. Inaddition to responding to keratinocyte-derived IL-1, fibroblasts canalso be directly activated by the triggering stimulus (e.g. UVR) andthis further stimulates the expression of pro-inflammatory genesresulting in the production of PGE-2, the chemokine IL-8, as well ascollagenase-1 (MMP-1). IL-8 stimulates diapedsis (chemotaxis, movement)of neutrophils, monocytes and ultimately lymphocytes from theendothelial cells where they have attached as a result of the TNF-ainduced increase in adhesion molecules. Once in the tissue, neutrophilsand monocytes produce additional cytokines (IL-1, IL-12), and chemokinesincluding monocyte chemotactic protein (MCP-1), a potent chemokine thataccelerates the movement of monocytes into the tissue and helpstransform them into macrophages. Mature macrophages in turn produce avariety of matrix metalloproteinases (MMPs) that degrade extracellularmatrix proteins and thus reduce the strength, elasticity and thicknessof the skin.

If the inflammatory response is maintained by the continued presence ofan antigen in the skin as is the case with chronic and destructivecutaneous diseases such as psoriasis and atopic dermatitis, thepersistence of the antigen causes T-lymphocytes to enter the tissue siteand become activated. This activation leads to the production ofcytokines such as TNF-α, monocyte chemotactic protein-1 (MCP-1), IL-8,IL-12, and interferon-γ (INF-γ). Released IL-12 causes the T-lymphocytesto proliferate rapidly and to produce a wide range of cytokines, growthfactors and other inflammatory mediators. These released productsfurther activate macrophages, recruit monocytes, increase tissuedestruction and cause accelerated and uncontrolled growth of skin cells,particularly keratinocytes. The result is pronounced skin inflammationwith redness, pain, itching and scaling of the skin as the keratinocytesmove rapidly to the surface and “flake off”. Further, the rapid sheddingof keratinocytes at the surface compromises the barrier function of thestratum corneum resulting in water loss and dry skin.

A common finding in inflammation is that cells in the skin respond toinflammatory stimuli by activating either one of two intracellularsignaling pathways (or in some cases both pathways). These pathways arecommonly referred to as the Stress Activated Kinase (SAK) pathway andthe NF-kB pathway. The SAK pathway leads to the activation of the AP-1transcription factor, which then binds to and activates severalinflammatory genes including COX-2, IL-6 and MCP-1. Activation of theNF-kB pathway results in NF-kB protein translocation to the nucleus andactivation of NF-kB driven inflammatory genes such as IL-8, MMP-1, TNF-αand the adhesion molecule, VCAM-1. Interestingly, many inflammatorygenes including IL-1 have promoter elements that bind both AP-1 andNF-kB transcription factors and are thus regulated to some extent byboth signaling pathways. The Cutanix screening assays are designed todetermine which pathway is blocked by the compound under investigation,or if both pathways are effectively inhibited. A compound with thecapacity to block the transcription of inflammatory genes regulated byeach of these pathways will likely provide significant anti-inflammatoryeffects when applied topically. For each putative anti-inflammatorycompound under consideration the initial screening program concentrateson the following target sites for intervention:

1. Inhibiting the production of IL-1 and PGE-2 in UVR or tetradecanolyphorbol acetate (TPA)-treated keratinocytes.

2. Inhibiting the production of PGE-2 in UVR-treated dermal fibroblasts.

3. Inhibiting the induction of PGE-2 in IL-1 treated fibroblasts.

Because one of the most common activators of skin inflammation issunlight, specifically UVB radiation, the determination of a compound'sability to block the induction of pro-inflammatory PGE-2 by UVR in bothkeratinocytes and fibroblasts represents a logical first step in thescreening process. In addition, because skin inflammation is oftentriggered by contact with chemical irritants or allergens, the use ofTPA, which is known to trigger an inflammatory response in the skin,provides an additional model for the analysis of anti-inflammatoryactivities of test compounds. Finally, because IL-1 is one of the mostimportant mediators and propagators of inflammation and is rapidlyinduced by an inflammatory stimulus, such as UVR, determining theability of a potential anti-inflammatory compound to block either theproduction or action of IL-1 is a critically important initial screeningstudy. As shown in FIGS. 1 and 2, by blocking IL-1 production fromkeratinocytes, not only is the activation of fibroblasts suppressed butthe activation of mast cells is also blocked thus preventing the releaseof histamine and other inflammatory mediators. Furthermore, inhibitionof IL-1 production in the skin would prevent the activation of a largenumber of inflammatory genes that are stimulated solely by IL-1. Theseinclude COX-2, MMP-1, and a variety of cytokine and chemokine genes.

For all of the initial screening studies described herein, cells inculture are exposed to the appropriate agonist, (i.e. UVR, TPA or IL-1)and then incubated in medium for 24 or 48 hours in the presence orabsence of the compound under investigation. At 24 and 48-hour timepoints, medium from the cells is removed and assayed for a number ofinflammatory mediators by ELISA.

Only primary keratinocyte and fibroblast cell strains were used, notimmortalized cell lines, for the screening studies. The use of normalcells from the skin increases the probability that results from in vitrostudies will be predictive of effects of a given compound when appliedtopically.

Aldehydes that are found to completely (100%) suppress PGE-2 inductionat a concentration of 100 micromolar or less are then subjected to moredemanding dose-response studies including the following sequence ofexperiments:

1. Assessment by ELISA of a compound's ability to block a variety ofUVR, TPA, or IL-1 induced inflammatory mediators in keratinocytes andfibroblasts including IL-6, TNF-α, IL-8, and MMP-1.

2. Assessment by ELISA of a compound's ability to block the productionand secretion of inflammatory mediators by monocytes (THP-1 monocyteline) stimulated by lipopolysaccharide (LPS) and by T lymphocytes(Jurkat cells) stimulated with an antibody ligand that activates thecells.

3. The use of RPA (ribonuclease protection analysis) to determine if acompound is acting at the gene level to suppress the activity ofspecific inflammatory genes stimulated by exposure of cells to variousagonists including UVR, IL-1, TPA, or LPS (lipopolysaccharide). Cutanixhas developed a customized RPA “cocktail” for keratinocytes,fibroblasts, T-cells, and monocytes to simultaneously measure theexpression of cell-type specific inflammatory genes in cells stimulatedwith UVR, IL-1, TPA or LPS in the presence or absence of the compoundunder investigation.

4. The use of microarray gene analysis to simultaneously examine theeffect of any compound on the expression of more than 5,500 genesspecific for cells present in the skin. The gene arrays used werepurchased from Research Genetics and provide read-outs on genes known tobe expressed in the skin.

The aldehydes can suppress a number of pro-inflammatory mediators andFIG. 2 identifies some of the events that are likely inhibited by thealdehydes in vivo (shown by the circled X).

EXAMPLES

The following examples are provided to further describe the inventionand are not intended as limitations on the scope of the invention whichis defined by the appended claims.

Example 1

An initial in vitro experiment was conducted to demonstrate the activityof the aromatic aldehyde, 4-ethoxybenzaldehyde, (“4-EB”) as a topicallyadministered pharmaceutical.

For this experiment, human skin fibroblasts were seeded into 12 wellculture dishes at a density of 80,000 cells/well in tissue culturemedium and left overnight to attach to the dish. The next day, mediumwas removed and replaced with fresh medium containing either 1% ethanolas a diluent control, IL-1 at a concentration of 500 picograms/ml, orIL-1 plus 4-EB at either 250 μM or 500 μM. Cells were incubated for anadditional 24 hours and at this time, the medium was removed and assayedby ELISA for the presence of PGE-2 in the culture medium. The resultsshow that IL-1 caused a 17.8 fold increase in PGE-2 (control=727 pg/10⁶cells: IL-1=12,976 pg/10⁶ cells). However, cells treated with eitherconcentration of 4-EB showed a complete inhibition of the IL-1 inductionof PGE-2.

Example 2

Subsequent studies were carried out to determine the dose-response ofhuman skin fibroblasts to 4-EB. 4-EB completely blocked the IL-1induction of PGE-2 at 100 μM, blocked 82% of the PGE-2 induction at 50μM, and blocked 35% at a concentration as low as 10 μM. The results ofthe study are provided graphically in FIG. 3.

Example 3

Subsequent in vitro experiments were conducted to demonstrate theactivity of other aromatic aldehydes compared to the4-ethoxybenzaldehyde, (“4-EB”) as a topically administeredpharmaceuticals. The compounds tested were 2-ethoxybenzaldehyde (2-EB),3-ethoxybenzaldehyde (3-EB), and 4-methoxy-benzaldehyde (4MB).

For this experiment, human skin fibroblasts were seeded into 12 wellculture dishes at a density of 80,000 cells/well in tissue culturemedium and left overnight to attach to the dish. The next day, mediumwas removed and replaced with fresh medium containing either 1% ethanolas a diluent control, IL-1 at a concentration of 500 picograms/ml, orIL-1 plus one of the compounds under investigation at a concentration of1, 10, 50 or 100 μM. Cells were incubated for an additional 24 hours andat this time, the medium was removed and assayed by ELISA for thepresence of PGE-2 in the culture medium. The results show that IL-1caused a 4 to 22 fold increase in PGE-2.

Percent inhibitions as shown in the detailed results of FIG. 4A) are asfollows: 2-EB, 82.9% and 58.9% at 100 μM and 50 μM; 3-EB, 41.2% and42.6% at 100 μM and 50 μM; 4-EB, 81.5% at 100 μM.

Concentrations of 10 or 50 μM 4 MB did not appear to inhibit the IL-1induced production of PGE-2 in the fibroblasts. Percent inhibitions asshown in the detailed results of FIG. 4B) are as follows: 4-MB, 13.6%and 16.2% at 50 μM and 10 μM.

Example 4

Similar in vitro studies as those described in Example 3 were run usinghuman skin keratinocytes. The experimental set up was the same asdescribed for Example 3 but replacing IL-1 with tetradecanoyl phorbolacetate (TPA) at a concentration of 32 nM as the agonist. The compoundstested were 2-ethoxy-benzaldehyde (2-EB), and 3-ethoxybenzaldehyde(3-EB) and 4-ethoxybenzaldehyde (4-EB) in concentrations of either 10,50, or 100 μM. The results show that TPA caused a 3.5 fold increase inPGE-2. However, treatment with any of these compounds blocked PGE-2production by at least 50%.

The percent inhibitions as shown in the detailed results in FIG. 5 areas follows: 2-EB, 83%, 76.6%, and 55.2% inhibition at 100 μM, 50 μM, and10 μM; 3-EB, 76.7% and 57.7% at 100 μM and 50 μM; 4-EB, 94.9% and 79.9%at 100 μM and 50 μM.

Example 5

In vitro experiments were conducted to demonstrate the activity of aseries of aromatic aldehydes as a topically administeredpharmaceuticals. The compounds tested and the measured results aretabulated in FIG. 6, and shown graphically in FIGS. 8-11. These datainclude results for aldehydes of Formula I and also include results forother related compounds.

For this experiment, human skin fibroblasts were seeded into 12 wellculture dishes at a density of 80,000 cells/well in tissue culturemedium and left overnight to attach to the dish. The medium was thenreplaced with PBS for a challenge with either UV-light or with IL-1.After irradiation or introduction of IL-1, the PBS was removed andculture medium containing the appropriate compound (or DMSO forcontrols) was then added and the cells cultured for an additional 24hours. At that time, the medium was removed and assayed by ELISA for thepresence of PGE-2, IL-1, IL-6, IL-8, or MMP-1 in the culture medium. Thelevels of protein in the conditioned medium were measured and reportedas percent inhibition relative to diluent controls.

IL-1 Challenge

On the second day, the medium was removed and replaced with fresh mediumcontaining either 1% ethanol as a diluent control, IL-1 at aconcentration of 500 picograms/ml, or IL-1 plus one of the compoundsunder investigation at a concentration of 100, 10, or 1 μM.

UV-Light Challenge

On the second day, the medium was removed and replaced with fresh PBSfor irradiation. The fibroblasts were then irradiated with 50 mJ of UVB.UVB irradiation was obtained by illuminating the samples with an FS-20sunlamp through the lids of the multi-well plates in order to filter outthe UVC radiation. After irradiation the PBS solution was removed andreplaced with a solution containing either 1% ethanol as a diluentcontrol, or one of the aldehyde compounds at a concentration of 100, 10,or 1 μM. The cells were incubated for another 24 hours and the mediumwas then removed for the ELISA assays and the cells were counted.

Example 6

Similar in vitro studies as those described in Example 5 were run usinghuman skin keratinocytes. The experimental set up was the same asdescribed for Example 5. The products assayed by ELISA for the presenceof PGE-2, IL-1, IL-6, IL-8, MMP-1, or TNF-a in the culture medium.

For the cells challenged by a biochemical agonist, IL-1 was replacedwith tetradecanoyl phorbol acetate (TPA) at a concentration of 32 nM.When UV-light was used to challenge the cells, they were exposed to 75mj of UVB, obtained by illuminating the samples with an FS-20 sunlampthrough the lids of the multi-well plates in order to filter out the UVCradiation.

The compounds tested were in concentrations of either 100, 10, or 1 μM,and the protein expression levels are reported in percent inhibition ofgrowth.

The measured percent inhibitions are tabulated in FIG. 7 and showngraphically in FIGS. 12-14.

Example 7

Because of the marked anti-inflammatory effects seen when 4-EB was usedin human fibroblast cell culture models, in vivo studies were carriedout to determine if topically applied 4-EB could block an inflammatoryresponse in humans. While the details provided herein are for a specificcompound, the same tests can be used on any of the aromatic aldehydes ofthe present invention.

A topical lotion was developed for 4-EB which consists of the following:

Aqueous Phase

Deionized water 57.6% (by weight) Niacinamide 2.0% Glycerin 4.0%Phenonip 1.0%

Oil Phase

Propylene glycol 5.0% Transcutol 3.2% Jojoba Oil 3.5% Isocetyl alcohol2.0% Isocetyl Stearate 3.5% Mineral Oil 3.0% 4-ethoxybenzaldehyde 1.0%Isostearyl Palmitate 3.0% PEG-7 Glyceryl Cocoate 2.0% Glycereth-7 2.0%Polysorbate-20 ™ 0.2% Cetyl Ricinoleate 1.0% Glyceryl Stearate/ 4.0%PEG-100 Stearate

Thickener

Sepigel ™ 2.0%

This lotion was then tested by Franz cell percutaneous absorptionanalysis to determine how much 4-EB could penetrate human skin over a 24hour period. The lotion formulation above provided a flux rate of 4-EBthrough human skin of 30-50 micrograms/ hour.

This lotion was then tested to determine if it could prevent aninflammatory response when applied topically to human skin. For thisstudy a lab volunteer was irradiated on a quarter sized spot on theinner forearm with 60-80 mJ of UVB light (a sunlamp). This dose wassufficient to cause a highly visible red erythema response Immediatelyfollowing irradiation on both arms, one arm was treated with the above4-EB lotion while the other arm was treated with the same lotionformulation but with no 4-EB. Within 2-6 hours after irradiation thevehicle-treated arm developed a pronounced red erythema response at thesite of irradiation while the 4-EB lotion treated spot did not. Even thenext day, 14 hours post-irradiation, the spot treated with 4-EB showedno redness. This study demonstrates that topically applied 4-EB hasmarked anti-inflammatory activity.

In addition to its anti-inflammatory activity compounds of the presentinvention, either alone or in combination with other compounds, such asethyl vanillin, may have anti-aging properties. One of the classicalsymptoms of skin aging is an increase in collagenase activity in dermalfibroblasts which destroys collagen thereby leading to sagging skin andwrinkles.

Implications of the Results in Terms of Potential Uses of the DiscoveryAnti-Ahing

The finding that aromatic aldehydes of the present invention inhibit theactivity of inflammatory genes in cultured skin cells and that they canblock an inflammatory response in vivo when applied topically suggestswide utility for these compounds in the cosmetic, dermatology and oraldrug markets. In the cosmetic market, these compounds when formulatedfor topical use can be expected to lower chronic sun-inducedinflammation, which causes the activation of genes in skin cells thatdestroy the skin matrix. By inhibiting sun-induced genes such as MMP-1(collagenase), gelatinase, and cytokines IL-1, IL-12, etc. 2-EB, 3-EBand 4-EB will prevent the further breakdown of the skin and thus lessenthe production of lines and wrinkles, sagging skin, and thinning ofskin. It is likely that these aromatic aldehydes will stimulate genesthat support the skin matrix such as collagen (studies ongoing). Thus,this product can be used as a “skin restorative” product for sun-damagedskin It has its utility in treating actinic keratoses by both preventingtheir formation and actually reducing the size and number of existingkeratoses.

Sun Care Products

The finding that topically applied 4-EB, or any other compound of thisinvention, can completely prevent the onset of a sunburn by UVB exposuresuggests the use of aromatic aldehydes in sun care products includingpre-sun, sun-tan lotions, and after-sun products. It is not suggestedthat the molecules have sun-screen properties (which they probably do tosome extent) but that they can actually arrest the progression of asunburn AFTER the skin has already been exposed to the UV rays of thesun. Although it has been shown that topical application of the productimmediately after UVB exposure will prevent the onset of sunburn, it isalso possible that application of the product even after the sunburn hasappeared may: 1) prevent the continued progression of sunburn, and 2)reverse the redness already present.

Example 8 Rosacea Clinical Study

The 30 subjects with mild to moderate rosacea were treated either withlotion containing 1% w 4-EB (20 subjects) or with a control lotion withthe active material removed. The study was randomized and doubleblinded. During their first visit, patients were evaluated using 4measurements of disease: 1) erythema, 2) desquamation (peeling), 3)uneven skin tone, and 4) dermatitis. The clinician also provided an“Overall Severity” score which ranged from 1-6 with 6 being the mostsevere level of overall disease. Patients were photographed to recordthe severity of the disease. After evaluation patients were sent homewith either the test lotion or the control lotion and told to apply itmorning and evening for two weeks. They then returned to the clinic fora two-week evaluation and at that time received more product for anadditional 2 weeks. At four weeks, both the clinician and the subjectsevaluated the severity of their disease. Digital photographs of thetreated areas were also taken.

Of the 30 rosacea patients that started the study, 28 completed thefour-week period. None of the subjects, including those who dropped out,experienced any irritation or other adverse effect from the product. Thebar graph of FIG. 15A summarizes the percentage improvement in “OverallSeverity” for the test lotion treated group at 4 weeks. As can be seen,the severity of rosacea decreased in 13/18 subjects (72%). Averageimprovement among those responding was 68% (49% for all patients). Thisis a statistically significant result.

The bar graph of FIG. 15B summarizes the percentage improvement in“Overall Severity” for the control lotion treated group at 4 weeks. Ascan be seen, the severity of rosacea decreased in 6/10 subjects (60%)but increased in 3/10 (30%). Average overall improvement was 15% whichis not a significantly significant result.

The test lotion also achieved another important statistical threshold inthe rosacea study. The degree of improvement in the test lotion treatedgroup was significantly better than the degree of improvement in thecontrol treated group (p=0.05) using both Wilcoxon and Analysis ofVariance statistics. These results are of sufficient quality to meetregulatory standards for drug efficacy and clearly establish the abilityof 4-ethoxybenzaldehyde to suppress skin inflammation in humans.

Rosacea is a difficult disease to treat because of the severity of skininflammation and vasodilation. Considering that a 2% formulation of 4-EBhas been shown to be more effective in blocking UV-induced erythema thanthe 1% formulation used in this clinical study, a higher strengthversion of the test lotion may provide even grcater efficacy in treatingrosacea.

1. A composition comprising (1) an effective skin-condition alleviatingamount of a first active ingredient selected from the group consistingof 2-ethoxybenzaldehyde, 4-allyloxybenzaldehyde, 4-ethoxybenzaldehyde,4-propoxybenzaldehyde, 4-butoxybenzaldehyde, 4-pentyloxybenzaldehyde,and 4-hexyloxybenzaldehyde; (2) niacinamide; and (3) a pharmaceuticallyor cosmetically acceptable topical carrier, wherein the skin-conditionis selected from the group consisting of skin inflammation, aging,sunburn microbial infection, psoriasis, acne, dandruff, hair loss,poison ivy, rosacea, and eczema.
 2. The composition of claim 1 in asustained release dosage form.
 3. The composition of claim 1, whereinthe first active ingredient is 4-ethoxybenzaldehyde.
 4. The compositionof claim 1, wherein the pharmaceutically or cosmetically acceptabletopical carrier is a lotion.
 5. The composition of claim 1, wherein thepharmaceutically or cosmetically acceptable topical carrier is a cream.6. A method for alleviating symptoms of a skin condition, comprisingtopically administering to said affected skin an effective amount of thecomposition of claim 1 to alleviate said symptoms, wherein the skincondition is selected from the group consisting of skin inflammation,aging, sunburn microbial infection, psoriasis, acne, dandruff, hairloss, poison ivy, rosacea, and eczema.
 7. The composition of claim 1,wherein the effective skin-condition alleviating amount of the firstactive ingredient selected from the group consisting of2-ethoxybenzaldehyde, 4-allyloxybenzaldehyde, 4-ethoxybenzaldehyde,4-propoxybenzaldehyde, 4-butoxybenzaldehyde, 4-pentyloxybenzaldehyde,and 4-hexyloxybenzaldehyde is between 0.001% to 20% by weight.
 8. Thecomposition of claim 3, wherein the effective skin-condition alleviatingamount of 4-ethoxybenzaldehyde is between 1.0% and 10% by weight.
 9. Thecomposition of claim 8, wherein the effective skin-condition alleviatingamount of 4-ethoxybenzaldehyde is 1.0% by weight.
 10. A transdermalcomposition, comprising a transdermal preparation of (1) an effectiveskin-condition alleviating amount of a first active ingredient selectedfrom the group consisting of 2-ethoxybenzaldehyde,4-allyloxybenzaldehyde,4-ethoxybenzaldehyde, 4-propoxybenzaldehyde,4-butoxybenzaldehyde, 4-pentyloxybenzaldehyde, and4-hexyloxybenzaldehyde; (2) niacinamide; and (3) a pharmaceutically orcosmetically acceptable carrier, wherein the skin-condition is selectedfrom the group consisting of skin inflammation, aging, sunburn microbialinfection, psoriasis, acne, dandruff, hair loss, poison ivy, rosacea,and eczema.
 11. The transdermal composition of claim 10 in a sustainedrelease dosage form.
 12. The transdermal composition of claim 10,wherein the first active ingredient is 4-ethoxybenzaldehyde.
 13. Thetransdermal composition of claim 10, wherein the pharmaceutically orcosmetically acceptable carrier is a lotion.
 14. The transdermalcomposition of claim 10, wherein the pharmaceutically or cosmeticallyacceptable carrier is a cream.
 15. A method for treating a patient witha skin condition, comprising administering to said patient an effectiveskin-condition alleviating amount of the transdermal composition ofclaim 10, wherein the skin-condition is selected from the groupconsisting of skin inflammation, aging, sunburn microbial infection,psoriasis, acne, dandruff, hair loss, poison ivy, rosacea, and eczema.16. The transdermal composition of claim 10, wherein the effectiveskin-condition alleviating amount of the first active ingredientselected from the group consisting of 2-ethoxybenzaldehyde,4-allyloxybenzaldehyde, 4-ethoxybenzaldehyde, 4-propoxybenzaldehyde,4-butoxybenzaldehyde, 4-pentyloxybenzaldehyde, and4-hexyloxybenzaldehyde is between 0.001% to 20% by weight.
 17. Thetransdermal composition of claim 12, wherein the effectiveskin-condition alleviating amount of 4-ethoxybenzaldehyde is between1.0% and 10% by weight.
 18. The transdermal composition of claim 17,wherein the effective skin-condition alleviating amount of4-ethoxybenzaldehyde is 1.0% by weight.